Benign prostatic hyperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) are common benign prostatic diseases in middle-aged and older men. The prevalence of BPH increases with age, affecting approximately 45% of men older than 45 years and nearly 80% of those older than 70 years. CP/CPPS predominantly affects men aged 30-50 years, with a global prevalence of approximately 8%. Conventional pathogenic models emphasize androgen metabolism, chronic inflammation, aging, and genetic susceptibility; however, these factors do not fully explain the marked clinical heterogeneity of these disorders. Recent evidence suggests that the gut microbiota may influence prostatic inflammation and hyperplasia through microbial metabolites, immune regulation, and neuroendocrine pathways, giving rise to the concept of a gut-prostate axis. Animal experiments and clinical association studies have reported significant differences in gut microbial composition between patients with BPH or CP/CPPS and healthy controls, and some studies have suggested that microbiota-directed interventions, such as fecal microbiota transplantation, may have potential for alleviating pelvic pain. This narrative review selectively synthesizes evidence from published systematic reviews and original studies to discuss the relationship between the gut microbiota and BPH and CP/CPPS, evaluate the proposed mechanisms and current controversies, and outline future research directions and translational prospects.

Although immune-targeted therapies, particularly agents targeting the IL-23/IL-17 axis, have markedly improved short-term disease control in psoriasis, inadequate responses in a subset of patients and relapse after treatment discontinuation remain unresolved challenges. One possible reason is that immune-centered therapies may not fully address the active contribution of epidermal keratinocytes (KCs) to inflammatory amplification and disease persistence. In this review, we integrate immune-driven inflammation and epidermal amplification mechanisms from a loop- and network-based perspective, and propose an immune-epidermal dual-targeting framework centred on pro-inflammatory feedback between immune cells and KCs. We systematically summarize three potential implementation routes: combination therapy, single-agent dual targeting and blockade of bridging nodes within immune-epidermal feedback circuits. We further discuss the potential roles and realistic boundaries of artificial intelligence and multi-omics analysis, organoids and engineered skin models, and precision local delivery technologies in target discovery, mechanistic validation and therapeutic translation. Importantly, this framework is not intended to replace existing therapeutic paradigms, but rather to refine their mechanistic interpretation and extend future therapeutic strategies. It may provide additional translational opportunities for stratified, stage-specific and precision management of psoriasis, although several components remain at the stage of mechanistic research and clinical validation.

SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) is a key epigenetic regulator that catalyzes histone H3 lysine 9 trimethylation (H3K9me3), a mark essential for transcriptional repression and heterochromatin formation. Here, we investigated the role of SETDB1 during zygotic genome activation (ZGA) in porcine embryos. SETDB1 knockdown (KD) was induced by microinjecting double-stranded RNA (dsRNA), and its impact on early embryonic development was evaluated. SETDB1 KD decreased H3K9me3 levels, markedly increased H3K9ac, and downregulated ZGA-associated genes. These epigenetic alterations were accompanied by impaired cleavage, reduced blastocyst formation, and a lower total cell number. Upon etoposide-induced DNA double-strand breaks, SETDB1 KD embryos showed reduced expression of key DNA repair proteins, failed to efficiently restore DNA integrity, and exhibited increased apoptosis, indicating a compromised DNA damage response and repair process. SETDB1 KD also reduced HDAC3 expression, suggesting that SETDB1 may regulate HDAC3 to maintain histone acetylation balance. Consistently, HDAC3 inhibition increased H3K9ac, decreased H3K9me3, and reduced SETDB1 protein levels, supporting a reciprocal regulatory relationship. Together, these findings indicate that SETDB1 is important for porcine embryonic development by coordinating histone modifications and safeguarding genomic integrity during ZGA, and they suggest that the interplay between SETDB1 and HDAC3 constitutes a potentially important epigenetic axis for proper histone modification dynamics and developmental competence.

Ghostwritten medical papers are a cornerstone of pharmaceutical marketing. We trace how one manuscript written under the instructions and supervision of opioid producer Mallinckrodt was produced and eventually published in a medical journal to present a marketing message. We systematically analyse an archive of internal communications made public after litigation through the lens of Ricœur's work on imaginaries. Along his first analytic axis, we show how the ghostwriting process shapes and reshapes identities, ascribing agency and portraying social order. Along the second, legitimacy was constructed by the expert voice of a peer-reviewed article 'authored' by researchers, but written by backstage medical writers. Third, the result was a twisted phantasmagory of both academic writing and pain management. Professional medical writers generated an imaginary of pain management to expand the prescription of opioids by redefining pain categories and reassigning agency and responsibility of actors in pain treatment. Meanwhile, backstage writers also reproduced an imaginary of scientific writing, with efficient writing as an editorial service that misrepresents authorial contribution and responsibility. We suggest that Ricœur's analytic scheme could also be used to disentangle technoscientific imaginaries in other settings.

Proboscideans exhibit limb morphologies specialised for supporting extreme body masses under predominantly compressive loading. These graviportal adaptations include repositioning of the limb bones closer to the trunk, resulting in a columnar stance. Among proboscideans, two humeral morphotypes have been proposed (slender and robust), yet their functional significance under compressive loading remains poorly understood. Finite element analysis (FEA) is applied to evaluate biomechanical performances of proboscidean humeri subject to axial compression, simulating conditions associated with a columnar stance and deviations from it. Our results reveal clear differences between morphotypes, with slender humeri performing worse than the robust morphotype and functioning optimally under near-axial loading. Robust humeri consistently exhibit lower peak stress under both neutral and off-axis loading and show considerable resistance to mediolateral stresses. Across all taxa, stress magnitudes generally increase when deviating from a neutral orientation, especially during posterior loading orientations, highlighting the mechanical importance of maintaining columnar limb posture. These findings support the hypothesis that robust morphologies are better adapted to resist multidirectional stresses, while slender morphologies favour energetic and locomotor efficiency. This study demonstrates the applicability of FEA in assessing compressive performance in postcranial elements and provides a novel framework for investigating biomechanical adaptations in graviportal taxa.

Triple-negative breast cancer (TNBC) is an aggressive malignancy with limited treatment options, highlighting the urgent need to identify novel therapeutic targets. The present study investigates the role of the RNA methyltransferase METTL3 in promoting TNBC progression by modulating a ferroptosis-related phenotype, an iron-dependent form of regulated cell death. Using TNBC cell lines (BT549 and MDA-MB-231), we demonstrated that METTL3 overexpression significantly enhanced cell proliferation, while its knockdown suppressed growth. Mechanistically, METTL3 was associated with decreased lipid peroxidation, reactive oxygen species (ROS), intracellular Fe2 + levels, and the pro-ferroptotic protein ACSL4, alongside increased glutathione and the key ferroptosis inhibitor GPX4. Bioinformatic analysis, MeRIP-PCR, and actinomycin D chase assays indicated that METTL3 was associated with increased N6-methyladenosine (m6A) enrichment, expression, and persistence of ELF1 mRNA. Dual-luciferase reporter assay further suggested that ELF1 may be involved in GPX4 transcriptional regulation. Crucially, the pro-proliferative and ferroptosis-associated effects of METTL3 overexpression were partially attenuated upon ELF1 knockdown or treatment with the ferroptosis inducer erastin. In conclusion, our findings suggest a novel METTL3/ELF1/GPX4 axis through which METTL3 promotes TNBC growth by regulating oxidative stress and ferroptosis-related markers, providing a basis for further investigation of this pathway in the context of TNBC biology and therapeutic development.

Migraine is a prevalent neurovascular disorder with a pronounced female predominance that cannot be fully explained by general pathophysiological mechanisms alone. Emerging evidence implicates interactions between estrogen and calcitonin gene-related peptide (CGRP) signalling as one potential contributor to sex-related differences in migraine susceptibility. This review synthesizes current mechanistic evidence on how estrogen modulates CGRP signalling, trigeminovascular sensitivity, and neuroimmune activation across the female lifespan, and examines the implications of this axis for pharmacological targeting. Evidence supports a state-dependent association between estrogen status and trigeminovascular excitability, with experimental studies indicating hormonal modulation of CGRP-related signalling, vascular reactivity, and neuroimmune pathways. Clinical and preclinical observations are consistent with increased migraine susceptibility during periods of estrogen withdrawal or instability; however, a direct causal sequence linking estrogen withdrawal to increased CGRP signalling and downstream neuroimmune activation in humans has not been established. Although current clinical data do not demonstrate consistent sex differences in the efficacy of CGRP-targeted therapies, hormonal state and reproductive life stage remain potential modifiers of treatment response that require prospective investigation. The estrogen-CGRP framework provides an integrative perspective on endocrine, neuroimmune, and pharmacological regulation in migraine. Integration of this framework into research design and clinical decision-making may improve the development of sex-informed, mechanism-based therapeutic strategies.

Germinal center (GC) B cells are critical for the production of long-lived plasma cells and high-affinity antibodies. Upon exiting the GC reaction, B cells differentiate into either memory B (MB) cells or plasma cells depending on affinity signals and transcription factor profiles. However, the underlying transcriptional and metabolic mechanisms regulating this fate decision remain poorly understood. Here, we generated mice with B and GC B-cell-specific knockout of heterogeneous nuclear ribonucleoprotein K (hnRNPK). We found that hnRNPK deletion partially impaired B-cell development and, more strikingly, markedly attenuated the GC B-cell response. The reduction in GC B-cell numbers was attributed to excessive differentiation of precursor MB cells and plasma cells during the GC reaction. Mechanistically, hnRNPK directly suppressed the expression of the key MB cell-associated transcription factors Hhex and Zfp318. Moreover, we observed that compared with CD25-negative GC B cells, CD25-positive GC B cells displayed elevated glycolytic gene expression and significantly increased glucose uptake. HnRNPK deficiency further upregulated glycolytic activity, promoted CD25 expression, and consequently enhanced plasma cell differentiation. Blocking IL‑2/CD25 signaling mitigated the excessive plasmablast differentiation induced by hnRNPK loss and rescued the GC defects in hnRNPK‑deficient mice. Together, these findings demonstrate that hnRNPK controls GC B-cell output by transcriptionally repressing the expression of the MB cell-differentiation factors Hhex and Zfp318 and by modulating the glycolysis‑CD25 regulatory axis.

Premature ovarian insufficiency (POI) is a heterogeneous disorder characterised by accelerated follicular depletion and ovarian dysfunction before age 40, yet effective therapeutic strategies remain limited. Here we identify the histone demethylase KDM3A (lysine‑specific demethylase 3A) as a critical protective factor in POI. We found that KDM3A expression is significantly downregulated in both granulosa cells from idiopathic POI patients and a cisplatin‑induced POI mouse model, and its levels correlate positively with serum AMH and oestradiol and negatively with FSH and LH. KDM3A‑deficient mice exhibited exacerbated cisplatin‑induced ovarian failure, with increased follicular atresia, elevated apoptosis, and hormonal imbalances, whereas ovarian‑specific KDM3A overexpression restored follicular development, oocyte quality, hormonal balance, and fertility. Mechanistically, chromatin immunoprecipitation sequencing identified ATP‑binding cassette sub‑family A member 7 (ABCA7) as a direct transcriptional target of KDM3A. KDM3A binds to the ABCA7 promoter, removes the repressive H3K9me2 mark, and activates ABCA7 transcription. KDM3A‑mediated ABCA7 upregulation preserves mitochondrial integrity, reduces oxidative stress, maintains mitochondrial membrane potential and ATP production, and suppresses granulosa cell apoptosis. Notably, ABCA7 overexpression alone phenocopied the protective effects of KDM3A, indicating that ABCA7 acts as a key downstream effector. Collectively, our findings uncover a previously unrecognised KDM3A‑ABCA7 epigenetic axis that safeguards mitochondrial homeostasis in granulosa cells. This pathway not only advances our understanding of POI pathogenesis but also provides potential molecular targets for therapeutic intervention in chemotherapy‑induced ovarian injury.